Critical Role of a Transcription Elongation Regulator in Mammary Gland Development and Mammary Tumorigenesis.

Abstract

Abstract For a long time transcriptional regulation was thought to primarily regulated at the stage of transcription initiation. However, recent genome-wide studies suggest that the majority of genes, both active and inactive, in human cells experience transcription initiation and many of them have RNA polymerase II (RNAPII) physically present at the promoter-proximal region. Thus, transcription elongation may represent a common but under-explored step for mammalian gene regulation. Cofactor of BRCA1 (COBRA1), which was first identified as a BRCA1-binding protein, acts as an integral subunit of the negative elongation factor (NELF) complex to stall RNAPII at the promoter proximal regions of multiple estrogen-responsive genes. COBRA1/NELF-B also shares a number of target genes for transcriptional regulation with BRCA1 in breast cancer cells. In support of its potential role in tumor suppression, its reduced expression is strongly correlated with metastatic breast cancer and knockdown of COBRA1 leads to elevated hormone-dependent transcription and accelerated cell proliferation both in vitro and in xenograft models.In order to get a better understanding of the molecular functions of Cobra1 in mammary gland, we employed Cre-lox system to delete mouse Cobra1 in the mammary gland. These mammary gland-specific Cobra1 knockout mice exhibit severe defects in alveologenesis and lactogenesis. These animals also show abnormal epithelial morphology specifically in the luminal compartment. Luminal epithelial population isolated from these mice using cell surface markers showed reduced colony forming ability both in 2-D and 3-D cultures. Molecular basis for the Cobra1-associated developmental defects and the possible impact of Cobra1 deletion on mammary tumorigenesis will be discussed. By linking regulation of transcription elongation with mammary gland-specific functions, our work establishes a new mode of gene regulation in mammary gland development. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1152.